Investigating energy homeostasis using in vivo imaging techniques
Author(s)
Hankir, Mohammed Khair
Type
Thesis
Abstract
Obesity is a major growing cause of death with no effective long-term treatment apart
from surgical procedures such as Roux-en-Y gastric bypass (RYGB). The sustained
weight loss following surgery is thought to be due in part to the increased levels of
circulating anorexigenic gut hormones such as peptide YY3-36 (PYY3-36). Peripheral
administration of PYY3-36 suppresses appetite in rodents and man and represents a
potential therapy for obesity however its effects on feeding are transient. Here I have
characterized a long-lasting PYY3-36 analogue; PYY3-36 latrotoxin (PYY3-36 (LT)) which
demonstrated greater longevity than PYY3-36 in acute feeding studies and that produced a
10% reduction in bodyweight following once daily peripheral administration in a one
month chronic feeding study performed on diet induced obese mice.
Manganese enhanced MRI (MEMRI) has been used previously to assess the effects of
nutritional status and gut hormones on brainstem and hypothalamic neuronal activity in
vivo. I revealed through the MEMRI technique that the anorexigenic hormone pancreatic
polypeptide (PP) modulates hypothalamic neuronal activity in fasted mice. Following this
work, I performed more in-depth MEMRI experiments that revealed differential temporal
effects of PYY3-36 and PYY3-36 (LT) on hypothalamic neuronal activity in fasted mice
after treatment that corresponded to the effects seen with these peptides in feeding
stuides. I also performed pharmacological MEMRI studies with the food additive
monosodium glutamate (MSG) and confirmed its excitatory effect on neurons of the
arcuate nucleus of the hypothalamus (ARC) following peripheral administration to mice.
Roux-en-Y gastric bypass has been shown to increase energy expenditure possibly via a
brown adipose tissue (BAT) mediated mechanism. I performed positron emission
tomography-computed tomography (PET-CT) experiments on a rodent model of RYGB.
I observed no differences in the activity of BAT of RYGB animals compared to shamoperated
controls, indicating means other than increased BAT activity account for the
weight loss seen in this bariatric model.
The work in this thesis demonstrates that long-lasting PYY3-36 analogues represent a
viable obesity therapy. Furthermore, I have further developed both MEMRI and PET-CT
techniques for the study of energy balance.
from surgical procedures such as Roux-en-Y gastric bypass (RYGB). The sustained
weight loss following surgery is thought to be due in part to the increased levels of
circulating anorexigenic gut hormones such as peptide YY3-36 (PYY3-36). Peripheral
administration of PYY3-36 suppresses appetite in rodents and man and represents a
potential therapy for obesity however its effects on feeding are transient. Here I have
characterized a long-lasting PYY3-36 analogue; PYY3-36 latrotoxin (PYY3-36 (LT)) which
demonstrated greater longevity than PYY3-36 in acute feeding studies and that produced a
10% reduction in bodyweight following once daily peripheral administration in a one
month chronic feeding study performed on diet induced obese mice.
Manganese enhanced MRI (MEMRI) has been used previously to assess the effects of
nutritional status and gut hormones on brainstem and hypothalamic neuronal activity in
vivo. I revealed through the MEMRI technique that the anorexigenic hormone pancreatic
polypeptide (PP) modulates hypothalamic neuronal activity in fasted mice. Following this
work, I performed more in-depth MEMRI experiments that revealed differential temporal
effects of PYY3-36 and PYY3-36 (LT) on hypothalamic neuronal activity in fasted mice
after treatment that corresponded to the effects seen with these peptides in feeding
stuides. I also performed pharmacological MEMRI studies with the food additive
monosodium glutamate (MSG) and confirmed its excitatory effect on neurons of the
arcuate nucleus of the hypothalamus (ARC) following peripheral administration to mice.
Roux-en-Y gastric bypass has been shown to increase energy expenditure possibly via a
brown adipose tissue (BAT) mediated mechanism. I performed positron emission
tomography-computed tomography (PET-CT) experiments on a rodent model of RYGB.
I observed no differences in the activity of BAT of RYGB animals compared to shamoperated
controls, indicating means other than increased BAT activity account for the
weight loss seen in this bariatric model.
The work in this thesis demonstrates that long-lasting PYY3-36 analogues represent a
viable obesity therapy. Furthermore, I have further developed both MEMRI and PET-CT
techniques for the study of energy balance.
Date Issued
2010
Date Awarded
2010-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Bell, Jimmy
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)